Funding opportunity HL-132 provides a mechanism to address the condition of heart failure with preserved ejection fraction (HFpEF), which afflicts millions of older Americans and is associated with exercise intolerance, reduced quality of life (QOL), high health care costs, and increased mortality. People with HFpEF display increased cardiac filling pressures and inadequate cardiac output reserve to deliver blood to the body during exercise. Numerous lines of evidence have implicated abnormalities in nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling as playing a key role in promoting these abnormalities. While there is currently no proven effective medical treatment for HFpEF, exercise training (ET) has been shown to improve aerobic ca- pacity and QOL in this population. However, ET provides benefits through peripheral effects without targeting the cardiac limitations. The long-term goal of this research is to identify novel treatments for HFpEF based upon detailed understanding of its pathophysiology. The specific objectives of this application are to determine whether treatment with sodium nitrite (NO2-) in addition to ET can improve exercise capacity, chronic activity levels, and QOL in people with HFpEF. The guiding hypothesis is that enhancing NO-cGMP signaling in the heart and periphery preferentially during exercise will improve functional capacity and symptoms in HFpEF above and beyond what is seen with ET alone. Conversion of NO2- to biologically active NO is enhanced during tissue hypoxia and acidosis, which develop during low-level exercise in HFpEF, so it is expected that this intervention will preferentially target the cardiac limitations that develop during exercise i these patients at the time of greatest need. This hypothesis will be tested by pursuing two specific aims: (1) Determine whether treatment with NO2- in addition to ET for 12 weeks improves exercise capacity and hemodynamic reserve in people with HFpEF as compared to placebo with ET, and (2) Determine whether treatment with NO2- in addition to ET for 12 weeks increases chronic daily activity levels and QOL, and reduces symptoms of effort intolerance during ET. Under the first aim, expired gas analysis, inert gas (C2H2) rebreathe and echocardiography will be performed at rest and during exercise to measure oxygen consumption, cardiac output responses and central hemodynamics to maximal effort exercise before and after completion of 12 weeks of ET with NO2- as compared to ET with placebo. Under the second aim, subjects will use externally-worn accelerometer devices to quantify chronic daily physical activity over the 12-week study, QOL will be assessed by questionnaire, and ET tolerability will be measured by perceived effort and dyspnea scores reported during ET sessions. This proposal is innovative and significant because it will allow for greater utilization and enhanced benefit from ET in people with HFpEF by using a novel class of medicine that we have shown to preferentially target cardiac abnormalities developing with exercise in a growing population of older Americans for whom there are few current treatment options available.